Using oxygen-15 water positron emission tomography to measure regional cerebral blood flow (rCBF), a marker of local neuronal activity, we have found that normal subjects performing tasks involving working memory use a cortical network including dorsolateral prefrontal cortex, inferior parietal lobule, and inferior temporo-occipital cortex. In other tasks related to prefrontal cortex, we have shown with a maze task that acquisition, but not retrieval of spatial data involves frontal cortex, particularly on the right; with word generation tasks semantic and phonologic cues activate similar brain regions including anterior cingulate, left frontal cortex, thalamus and cerebellum, but subtle differenes exist between them that are consistent with the lesion literature. Studies of normal monozygotic and dizygotic twins aimed at determining the degree of heritability of cognitively-related regional brain function had suggested that while there are more similarities between twins than between age and sex-matched unrelated individuals, the degree of genetic influence may not be large. This is confirmed with multivariate canonical correlation analysis. We also found that several different pathophysiological mechanisms underly cognitive changes in normal aging. In regions where physiological activity is normally suppressed when young subjects perform the tasks older subjects activate more, and, moreover, the more they activate (or fail to suppress), the worse they perform on the tasks. In other areas, where physiological activity is normally increased in young people performing the tasks, older subjects activate less; and the less they activate these regions, the more impaired their performance. We have also carried out several experiments aimed at exploring the working memory system in normals under conditions that have relevance for cognitive symptoms of schizophrenia. First, in a dual-task paradigm that may model patients' limited working memory capacity, a fundamental characteristic of prefrontal cortex was attenuated activation in the face of supramaximal demands for stimulus processing. Second, in experiments aimed exploring the effects of increasing working memory load, increasing the "working" (i.e. number of manipulations on remembered material) and the "memory" (i.e. the amount of material) within working memory produced markedly different patterns of activation within the frontal lobes. Increasing the amount of remembered material produced graded physiological responses primarily in areas that play a role in preparing a response within the motor domain, including verbal responses. Increasing the degree to which the remembered material was manipulated produced graded physiological responses in regions more classically associated with the working memory, including dorsolateral prefrontal cortex. Neurochemical mechanisms of cognitively-induced cortical signals were also investigated. When endogenous ovarian hormones, estrogen and progesterone, of young women were blocked with a synthetic gonadotropin releasing hormone agonist, the brain's physiological response to performing a frontal lobe task was attenuated. When estrogen or progesterone was pharmacologically "added back", the activation pattern in response to this cognitive challenge was normalized. The catecholamine system was also investigated with amphetamine in normal subjects during two different cognitive tasks, one which normally activates the prefrontal cortex and the other of which may depend more on other parts of the brain including the hippocampus. Amphetamine not only tended to improve performance, but also enhanced activity in areas needed for the specific task while dampening activity in other areas that may be less critical for that task. A double dissociation was demonstrated. During the prefrontally-related task amphetamine increased activity in the prefrontal cortex even more than usual and turned activity down in the hippocampus which is not normally activated during that task. During the other task amphetamine increased hippocampal activity even more than usual and turned it down in other areas, including the prefrontal cortex. In other words, the drug exaggerated the normal brain activity pattern needed in the context of that particular cognition.